Tamoxifen is the most common prescribed adjuvant therapy for breast cancer, and is taken daily by women throughout this nation and the world. The development of endometrial hyperplasia, cellular atypia, and new endometrial cancers are the most serious side effects of tamoxifen treatment. Our research team has been studying tamoxifen using endometrial and breast cancer cells grown in vitro, and our preliminary findings point to a novel mechanism by which tamoxifen causes cellular damage. An enzyme, flavin-containing monoxygenase 5 (FMO5), converts tamoxifen into a metabolic by-product tmf* that damages DNA. Tmf* binds to DNA and causes structural damage called adducts. Our preliminary data indicate that the production of FMO5 is controlled by the hormone progesterone, which in turn acts through the progesterone receptor. Progesterone receptors exist in two forms, A and B. Interestingly, we have shown that only the B form of the progesterone receptor stimulates the production of FMO5. We hypothesize that women who develop atypical endometrial growth or cancers in response to tamoxifen do so because their endometrial cells contain relatively high levels of the B form of the progesterone receptor, which under the influence of progesterone, stimulate the production of the enzyme FMO5. The steps in our hypothesis are: (1) Progesterone binds to progesterone receptor B - (2) Production of FMO5 - (3) Tamoxifen is metabolized into a reactive by-product, tmf* - (4) Tmf* binds to DNA causing structural damage (adducts) - (5) DNA mutations occur - (6) In rare cases, endometrial cancer develops. We now wish to test this hypothesis in patients. Using a safe and simple office technique, we have already begun to sample the endometria of women taking tamoxifen. We propose to test the endometrial samples for the presence of the B form of the progesterone receptor; we will then determine if FMO5 and DNA adducts indicative of structural DNA damage are increased. In addition, we will assay for estrogen receptors and other growth factors through which tamoxifen may act. Our long-term goal is to determine which factors best correlate with the eventual appearance of tamoxifen-induced endometrial abnormalities. By screening for these factors, we hope to identify those women who are at risk for developing endometrial cancer. A reliable screening test for endometrial cancer would make tamoxifen an even safer medicine for future generations of women who need it.